1. Field of the Invention
The present invention relates to glucose sensors and, more particularly, to a membrane that is useful in a glucose sensor as well as other applications employing enzymes in which efficient oxygen transport to the site of the enzyme would be desirable.
2. Description of Related Art
There is currently a considerable need for a glucose sensor that can accurately measure glucose levels in low oxygen environments, and more particularly, a sensor that can be readily implanted into a human where it will function for a prolonged time period. The primary impetus for such a device is the disease known commonly as diabetes. It has been known for well over fifty years that this disease is primarily a result of inadequate secretion of the hormone insulin by the islet or Beta cells of the pancreas. When uncontrolled, this disease often leads to serious metabolic imbalances as the elevated glucose level leads to ketosis and damaging alterations in blood pH. However, life threatening swings in blood glucose are now largely controlled by diet and daily injections of insulin.
For decades it has been realized that control of diabetes by insulin injection usually results in much wider swings in blood glucose level than are common in a normal individual. However, the conventional wisdom was that only extremes in blood glucose level need be avoided. Nevertheless, occasional insulin injections (i.e., one to several per day) are unable to duplicate the strict control of blood glucose afforded by a properly functioning pancreas which continually meters out just enough insulin to maintain stable and relatively low blood glucose levels.
Despite avoiding extremes in blood glucose level insulin-dependent diabetics suffer a whole host of other maladies that decrease both the quality and quantity of life. Diabetics experience frequent vascular disease that often result in amputation of limbs as impaired circulation prevents adequate blood flow. Abnormal vascular growth within the eye may result in intraocular bleeding, and retinal damage with progressive loss of vision. Nerve degeneration may lead to loss of sensation and other related problems. As home glucose tests became common, more and more data became available demonstrating the relatively poor control of blood glucose afforded by periodic insulin injections. At the same time, a growing number of clinical studies demonstrated that strict control of blood glucose reduces many if not all of the diabetes-related diseases previously mentioned. Many scientists and physicians now believe that greatly improved blood glucose control can largely eliminate the mortality and morbidity associated with diabetes.
Scientists are working on automatic insulin injection systems that deliver exogenously supplied insulin as needed to maintain precise blood glucose control. A self-regulating artificial insulin source is needed to limit the damage caused by diabetes. Many types of regulated injection systems, both implantable and external, are already available. The key problem continues to be the need for an accurate glucose sensor to control these injection systems. The need to continually monitor glucose levels to permit constant metered dispensing of insulin generally eliminates methods relying on blood samples. It is clear that an implantable glucose sensor that measures in vivo glucose levels is needed.
Although there are a number of technologies that could potentially be used to create an implantable glucose sensor, the most favorable method seems to be some type of amperometric method. The chemical reaction most commonly used in enzyme coupled glucose sensors is the glucose oxidase mediated catalytic oxidation of glucose by atmospheric oxygen to produce gluconolactone and hydrogen peroxide (equation 1): EQU C.sub.6 H.sub.12 O.sub.6 +O.sub.2 +H.sub.2 O.fwdarw.C.sub.6 H.sub.12 O.sub.7 +H.sub.2 O.sub.2 (1)
In the presence of excess oxygen, the quantity of hydrogen peroxide produced in this reaction will be a direct measure of the glucose concentration. The hydrogen peroxide is detected by being reoxidized by an electrode (anode) maintained at a sufficient positive potential (equation 2): EQU H.sub.2 O.sub.2 -2.sub.e.sup.- .fwdarw.O.sub.2 +2H.sup.+ (2)
The glucose detection process is dependent upon the measurement of electrons removed from hydrogen peroxide in equation (2). The electrode is normally formed from a noble metal such as gold or platinum, the usually preferred metal.
It is well known to those of ordinary skill in the art that other specific hydrogen peroxide producing oxidase enzymes can be used to produce sensors for other substances such as cholesterol (cholesterol oxidase), amino acids (amino acid oxidase), alcohol (alcohol oxidase), lactic acid (lactic acid oxidase), and galactose (galactose oxidase) to name only a few. While this approach operates effectively to measure glucose under laboratory conditions, there are major impediments to using this approach in an implantable glucose sensor. In particular, glucose is extremely soluble in biological fluids whereas oxygen is poorly soluble in these same fluids and must be carried by specialized biomolecules such as hemoglobin. As a result, many tissues of the human body have an oxygen concentration equivalent to about 2-5% oxygen in nitrogen or lower. There may be a ratio of glucose to oxygen as high as 100 to 1 in subcutaneous and peritoneal fluids. This means these tissues may contain only 1% of the oxygen required for glucose oxidase to quantitatively oxidize glucose for measurement purposes.
Furthermore, the glucose oxidase of a glucose sensor must be protected from processes and other macromolecules which might destroy or inhibit the glucose oxidase, from enzymes such as catalase which destroy hydrogen peroxide, from microbes which would digest the enzymes, and from soluble compounds such as ascorbate which would interfere with the either the enzymatic or electrochemical reactions. This protection is achieved by separating the glucose oxidase from biological fluids by a semipermeable membrane, The best known membranes that are capable of selectively excluding proteins such as catalase while allowing the entry of glucose are so-called dialysis membranes. These membranes are generally hydrophilic membranes containing pores that readily admit neutral molecules with molecular weights below about 5,000 Daltons. Common examples of these membranes are membranes prepared from various regenerated celluloses such a spectrapore or cuprophane, polycarbonate, cellulose esters, and polysulfones.
Unfortunately, while semipermeable membranes do a good job of excluding undesirable proteins, they also exclude oxygen. Some membranes such as those of teflon (perfluorocarbon resins) or of silicone rubber are permeable to oxygen, but these membranes are virtually impermeable to glucose, and hence, cannot be used to protect a glucose sensor. U.S. Pat. No. 5,322,063 to Allen et al. reports a new type of polyurethane membrane said to allow some glucose permeability while favoring oxygen permeability. This might represent one solution to the unfavorable glucose to oxygen ratio of human tissues; however, these membranes have not been widely tested as yet.
Because of a superabundance of glucose and a shortage of oxygen, an implanted glucose sensor will tend to be oxygen limited and, thus, effectively measure oxygen instead of glucose. That is, under ideal conditions where the glucose concentration is low, oxygen would be adequate so that an increase in glucose concentration would result in a concomitant and proportional increase in hydrogen peroxide and, therefore, measured current at the electrode. However, as the concentration of glucose increases, oxygen will ultimately become insufficient causing the measured current to plateau and become independent of glucose concentration. Above this plateau, the measured current reflects changes in oxygen concentration rather than glucose concentration.
Many workers have failed to take into account the high glucose to oxygen ratio of human tissues. There are at least two ways to solve this problem: one can attempt to reduce the concentration of glucose that reaches the glucose sensor and/or one can attempt to increase the amount of oxygen available at the glucose sensor. The level of glucose can be reduced either by providing a permeability barrier to glucose or by providing additional enzyme systems, besides glucose oxidase, to consume glucose. The polyurethane membrane mentioned above is an example of this approach.
Accordingly, there is a need for a glucose sensor, in particular, an implantable glucose sensor that can accurately measure glucose levels in low oxygen environments.